Thyroid Hormone Receptor Beta Induces a Tumor-Suppressive Program in Anaplastic Thyroid Cancer

The thyroid hormone receptor beta (TR beta), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRb is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TR beta levels decreased tumor growth supporting the concept that TR beta could function as a tumor suppressor. Yet, the TR beta tumor suppression transcriptome is not well delineated and the impact of TR beta is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TR beta expression in the human ATC cell line SW1736 (SW-TR beta) reduces the aggressive phenotype, decreases cancer stem cell populations and induces cell death in a T-3-dependent manner. Transcriptomic analysis of SW-TR beta cells via RNA sequencing revealed distinctive expression patterns induced by ligand-bound TR beta and revealed novel molecular signaling pathways. Of note, liganded TR beta repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted proapoptotic pathways. Our results further revealed the JAK1-STAT1 pathway as a novel, T-3-mediated, antitumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TR beta-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TR beta activation as a promising therapeutic option in cancers.